Method and apparatus for inducing the permeation of medication into internal tissue

ABSTRACT

A method and apparatus for selectively treating a targeted portion of internal body tissue of a patient by providing an internal electrode at a point adjacent the tissue to be treated and electrodes external to the patient&#39;s body. Fluid containing Ionic molecules is supplied to a location between the internal electrode and the external electrodes and an electric field radiating outwardly from the internal electrode to the external electrodes is created so that said fluid flows outwardly away from said internal electrode into the tissue to be treated.

This application is a continuation of Ser. No. 08/033,648, filed Mar.17, 1993, now abandoned which is a continuation of application Ser. No.07/520,033, filed May 7, 1990, now issued as U.S. Pat. No. 5,236,413.

FIELD OF THE INVENTION

The present invention relates to techniques and devices for inducing thepermeation of medication and the like into body tissue and organs.

BACKGROUND OF THE INVENTION

Iontophoresis has been utilized for many years for delivering medicationinto the body of a patient to diagnose and treat various ailments.Another related procedure iontohydrokinesis has been proposed forsimilar use. For example, iontophoresis has been utilized to deliverPilocarpine medication to diagnose cystic fibrosis, for the permeationof insulin through the skin, the introduction of steroids into joints totreat arthritis, to anesthetize the eardrum or eye, to treat plantarwarts with sodium salicylate, to treat canker sores in the mouth withsteroids, to treat Peyronie's disease (the fibrosing of the penis), andto deliver procainamide across the heart during experimental open chestsurgery in dogs.

Iontophoresis involves the transportation of medication in the form ofnaturally charged or ionic molecules by creating an electric field whichacts as a driving force to cause the molecules to advance toward anoppositely charged pole. More particularly, iontophoresis is defined inSteadman's Medical Dictionary as the introduction by means of electriccurrent of ions of soluble salts into the tissues of the body fortherapeutic purposes; alternatively, the facilitated entry ofelectrically charged drugs into the surface tissue by application of anelectric current. For example, if fluid having charged molecules isplaced on a patient's skin and a properly oriented electric field isdeveloped, the fluid will permeate the patient's skin. Where themolecules normally are uncharged, they may be rendered ionic by loweringor raising the pH of the carrying fluid.

The principle is similar for iontohydrokinesis which may be used todeliver uncharged, non-polar molecules of medication. Iniontohydrokinesis, water, which has naturally charged molecules andcontaining noncharged or non-polar molecules of medication, istransported into the tissue of a patient. By subjecting the mixture toan electrical field, the water molecules will carry the unchargedparticles with them as they flow from one pole towards the other.

Typically the technique for developing the electric field iniontophoresis or iontohydrokinesis involves placing both positive andnegative electrodes externally of the patient's body or the specificorgan that is to be treated. Consequently, the techniques do not lendthemselves to targeted, localized treatment of internal body organs.

Generally, when it has been desired to use the procedure locally on aninternal organ, it has been necessary to expose the organ surgically.Once the organ is exposed, the electrodes can be placed on oppositesides of the organ, as in the case of the delivery of procainamide tothe heart during open chest surgery, discussed above. Such a surgicaltechnique for localized treatment of internal organs has obviousdrawbacks such as trauma to the patient and other disadvantages andrisks of general surgery. It would be desirable, therefore, to provide aless invasive technique for delivering an effective concentration ofmedication locally to an internal organ. For example, it would bedesirable to deliver concentrations of selected compounds to the wall ofan artery as an adjunct to angioplasty, a procedure to enlarge anarrowed (stenosed) portion of an artery by placing a balloon in thestenosis and inflating the balloon to dilate the stenosis, thusimproving blood flow through the artery.

A significant problem in angioplasty is the relatively high rate ofrestenosis (approximately 30%) after performing an initial angioplasty.It has been suggested that restenosis may be controlled or possiblyprevented by applying suitable medication to the wall of the artery inthe region of the angioplasty. For example, among the factors thought tocontribute to incidence of restenosis is the uncontrolled proliferationof smooth muscle cells in the arterial wall, as a consequence of theangioplasty. To that end, it has been proposed that a concentrated doseof suitable medication, such as heparin, be applied to a local region ofan artery and forced into the wall of the artery under pressure. Acatheter adopted for that purpose is disclosed in U.S. Pat. No.4,636,195 issued Jan. 13, 1987 to Wolinsky. The Wolinsky patentdescribes a catheter having a pair of spaced balloons mounted on thedistal end of the catheter. The catheter is inserted into the patient'sarteries and is navigated to the site of the angioplasty. The catheteris positioned so that the balloons embrace the region of theangioplasty. Suitable medication, such as heparin, then is forced, underpressure, into the space between the inflated balloons to force themedication, under pressure, into the wall of the artery.

It is among the objects of the invention, therefore, to provide aminimally evasive technique for delivering an effective concentration ofmedication or the like locally to an internal organ of the patient.

SUMMARY OF THE INVENTION

In accordance with the invention, medication or the like is cause topermeate through the tissue of a specific, targeted internal body organusing iontophoresis or iontohydrokinesis techniques. Practising theinvention involves placing one or more electrodes externally of andcircumferentially about the patient. Another electrode is inserted, asby a catheter, into the target organ or a selected portion of the organ.While an electric field is developed between the internal and externalelectrodes, medication having charged or polar molecules (iontophoresis)or uncharged molecules coupled with polar molecules, such as water(iontohydrokinesis), then may be delivered directly to the internalorgan at a location between the internal and external electrodes. Theelectric field will cause the medication to permeate radially outwardlyfrom the internal electrode toward the external electrodes thus causingthe medication to permeate through the target organ.

One embodiment of the invention adapted for use in treating the wall ofa blood vessel or other body lumen employs a balloon catheter which maybe placed in the blood vessel and positioned by inflating the balloon inthe specific portion to be treated. The catheter carries an internalelectrode which may be in the form of an insulated wire extendingthrough the catheter and terminating in the exposed electrode inside theballoon. The balloon which also acts as a drug reservoir has a pluralityof regularly spaced minute pores. The interior of the inflatable balloonis in communication with a source of liquid medication by a lumen thatextends through the catheter from the proximal end where the lumen canbe connected to the liquid source. Medication (ionic or coupled to acharged liquid molecule) is delivered to the balloon and weeps throughthe minute pores during generation of the electric field. When usedadjacent the heart, the electric field may be pulsed on during systoleto reduce the risk of inducing cardiac arrhythmia.

It is among the objects of the invention to provide a method of inducingpermeation of medication to a selected internal organ or body tissue.

Another object of the invention is to provide a method for treating abody organ with a substantial concentration of medicine or drugs,without systematically exposing the patient to such a concentration.

A further object of the invention is to provide a method and apparatusfor permeating the wall of an artery with suitable medication so as toreduce the risk of restenosis after angioplasty as well as a primarytreatment of obstructive coronary artery disease.

Another object of the invention is to provide a selective medicationdelivery technique for internal organs using principles of iontophoresisand iontohydrokinesis.

A further object of the invention is to utilize external electrodes andan electrode located in a targeted body organ for creating an electricfield to induce the permeation of medication into the targeted bodyorgan by iontophoresis or iontohydrokinesis.

DESCRIPTION OF THE DRAWINGS

The foregoing and other objects and advantages of the invention will beappreciated more fully from the further description thereof, withreference to the accompanying drawings wherein:

FIG. 1 is a diagrammatic illustration of a system for practising oneembodiment of the invention including a balloon catheter having apermeable balloon and a "driving" electrode, and an external "return"electrode;

FIG. 2 is a cross-sectional illustration of the catheter shaft in a twolumen embodiment of the invention;

FIG. 2A is a cross-sectional illustration of the shaft of the catheterin a three lumen embodiment of the invention in which the balloon is incommunication with two lumens including an inlet lumen and a returnlumen;

FIG. 3 is an enlarged diagrammatic illustration of the catheter inaccordance with the invention illustrating the balloon and electrodeconfiguration at the distal end of the catheter;

FIG. 3A is an illustration similar to FIG. 3 illustrating the distal endof the catheter or a three lumen device of the type illustrated in FIG.2A; and

FIG. 4 is a diagrammatic illustration of a patient having multipleelectrodes placed circumferentially outside the body.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 illustrates apparatus as it may be used in the practice of theinvention. The apparatus includes a catheter 10 and an external returnelectrode 13. Although only one external electrode 13 is illustrated inFIG. 1, multiple external electrodes preferably are employed and areplaced circumferentially about the patient as illustrated in FIG. 4.

As illustrated diagrammatically in FIG. 1, the catheter includes anelongate flexible shaft 12 that may be formed from any of a variety ofpolymeric materials commonly used in catheter manufacture. The catheter10 has a proximal end (to the left in FIG. 1) that remains outside ofthe patient and a distal end (to the right in FIG. 1) that is insertedinto the patient. An inflatable and deflatable balloon 14 is mounted tothe distal end of the catheter shaft 12. The proximal end of thecatheter shaft may branch out into two or three proximal legs includingan inflation/deflation leg 16 and a guidewire leg 18 (in the two legembodiment) and a third fluid return leg 20 (in the three legembodiment). It should be noted that in the two leg embodiment, returnleg 20 is omitted, all three legs 16, 18, 20 being shown in FIG. 1 forconvenience of illustration. The catheter may have two or three lumens.

FIG. 2 illustrates, diagrammatically, the cross-sectional configurationof the catheter shaft 12 in a two leg, two lumen embodiment. In thisembodiment, the catheter shaft 12 includes an inflation lumen 22 and aguidewire lumen 24. The inflation lumen 22 is in communication with thetubular inflation leg 16 which, in turn, is connected to aninflation/deflation device 26 which may be any of a variety of suchdevices as are commercially available. The distal end of the inflationlumen 22 opens into the interior of the balloon 14, as indicateddiagrammatically at a port 28 in FIG. 3, Thus, the balloon 14 may beinflated and deflated through the lumen 22 by operation of theinflation/deflation device 26. As will be described in further detail,the balloon is formed to include a multiplicity of minute pores 30 whichmay be substantially regularly spaced about the surface of the balloon14. The pores 30 serve to deliver the medication to the wall of theorgan being treated. The other, larger lumen 24, is connected to thetubular guidewire leg 18 and serves to receive a guidewire 32. Theguidewire lumen extends fully the length of the catheter shaft, andterminates at a distal exit orifice 34. The guidewire 32 thus can beprojected distally beyond the distal end of the catheter shaft and maybe manipulated to facilitate placement of the catheter in the body lumenas will be appreciated by those familiar with the art. For example, theguidewire may be of the steerable type as described in further detail inU.S. Pat. No. 4,545,390 (Leafy).

In order to develop the electrical field necessary for iontophoresis oriontohydrokinesis, the catheter includes a conductor that extends fromthe proximal end of the catheter to and into the balloon 14. In theillustrative embodiment, the conductor is in the form of an insulatedwire 36 that may merge into the inflation/deflation lumen 22 at theproximal end of the catheter and may extend distally through the lumen22 and into the balloon. The distal portion of the conductor 36 disposedwithin the balloon 14 may be uninsulated to define the inner, drivingelectrode. Preferably, the driving electrode is wrapped helically aboutthe portion of the shaft 12A that extends through the balloon 14. Thehelical configuration of the electrode enhances uniform radialdistribution of the electrical field. In alternative embodiments, theconductive wire may be conducted to one or more metallic band electrodesextending about the shaft within the balloon, for example, as to amid-balloon marker band 38. Alternately, the electrode may be in theform of a wire mesh within the balloon about the catheter shaft.

In the three leg embodiment of the catheter, the catheter includes threelumens as indicated in FIG. 2A. In this embodiment, the catheter shaft12A is formed to include an inflation lumen 22A, a guidewire lumen 24Aand a return lumen 40. The proximal end of the return lumen 40 isconnected to the tubular return leg 20 at the proximal end of thecatheter. The distal end of the return lumen 40 opens into the interiorof the balloon at a port 42 illustrated in FIG. 3A. As will be describedfurther below, the three leg embodiment enables a continuous flow ofliquid into and out of the balloon 14.

The size of the balloon 14 is selected so that when inflated it will beslightly larger than the body lumen into which the catheter is to beinserted. This is desirable in order that the balloon may be pressedlightly against the inner luminal surface of the targeted organ so thatmedication that is emitted from the balloon will be applied directly andintimately against the inner luminal surface of the organ. The minutepores 30 may be of the order of 400 angstroms to 25 microns in diameter.The balloon 14 preferably is made of an inelastic polymeric material ofthe type used in balloon angioplasty catheters as will be familiar tothose skilled in the art. For example, the balloon may be formed frompolyethylene terephthalate. The inelasticity of the balloon materialserves to prevent the pores 30 from becoming too large during inflationof the balloon, thus undesirably varying the flow rate of themedication.

The external return electrodes 13 and the internal driving electrode areconnected to a direct current source 44. In order to reduce the risk ofdisrupting the patient's heart rhythm when the electrodes are in theregion of the heart, the current to the electrodes preferably is pulsedon during the systole phase of the cardiac pumping action and off duringdiastolic phase.

In use, the external electrodes 13 are positioned circumferentiallyabout the patient. The catheter 10 is inserted into the patient andmanipulated into the desired location of the desired body lumen. Thecatheter 10 may be positioned by any one of numerous well-known methodssuch as the use of guidewire 32. Once the catheter 10 has been advancedso that the balloon 14 is at the desired location, the balloon 14 isinflated to fill the body lumen and seal the balloon against the innersurface of the body lumen under light pressure. Preferably, the balloonis pressurized not substantially more than approximately 150 mmHg. Powerto the electrodes is provided to develop an electric field radiatingoutward from the inner driving electrode to the outer return electrodes13. Due to the charged nature of the medication or the water with whichthe medication may be mixed, the medication flows radially outward alongthe lines of the electric field, thus permeating the targeted tissuelocated radially outward from the balloon 14. The medication thus islocalized to the target organ.

The external electrodes 13 are positioned, as shown in FIG. 4, about thepatient's exterior so that the medication will flow radially outward inall directions. The charge applied to each of the electrodes may bevaried when the internal electrode is not located centrally inside thepatient so that the field is of equal strength through 360°. The currentstrength, duration of current application and location of the externalelectrodes may be varied to further focus the flow of medication. Patchelectrodes, which are known in the art, may be used as the externalelectrodes. Thus, the direction and uniformity of dispersion andpermeation of the medication may be controlled. The polarity of theinner driving and external return electrode is selected with referenceto the sense of the ionic compound to assure dispersion in a radiallyoutward direction.

The method and apparatus of the present invention provide numerousadvantages. By utilizing the electrode configuration of the presentinvention, specific internal locations of a patient may be targeted fortreatment with a particular medication. Furthermore, the permeation ofthe medication into the body tissue external the balloon is induced bycreating an electric field and not by increasing pressure on the liquidin the balloon 14. Consequently, mechanical stress to the body lumen iskept at a minimum. By introducing the medication to the balloon and onlyallowing it to pass radially outward through the balloon pores, anexcessive concentration of medication is not introduced to the patient.

While the foregoing method and apparatus are applicable to a widevariety of body organs and lumens, they have particular use in bloodvessels such as arteries. The catheter 10 shown in FIG. 1 may be used inthe primary treatment of a lesion (stenosis) with an appropriatemedication to reduce the size of the lesion or to prevent restenosisafter an angioplasty. In primary treatment of a lesion, the catheter 10is inserted into an artery until the balloon 14 is positioned againstthe region of the dilated stenosis. A suitable liquid medication (ionicor coupled to a polar carrier molecule) is infused into the balloon 14to inflate the balloon and seal it against the luminal surface. Anelectric field then is induced between the internal driving electrodeand the external return electrodes 13 so that the medication flowsradially outward through the pores 30 of the balloon 14 and into thearterial wall to break down the stenotic material and cause reduction inthe size of the stenosis.

When used for treating an artery after a conventional angioplasty toprevent restenosis, an antirestenosis drug, such as heparin, is used toinflate the balloon 14. Once the electric field has been induced, theheparin or other appropriate medication will flow outwardly and permeatethe arterial wall. The degree to which the medication permeates the wallcan be controlled by varying the strength of the electric field and thelength of time that the electric field is maintained. In the illustratedcatheter, the inflation of the balloon 14 shuts off blood flow throughthe artery during the procedure. The present method may be employed inan autoperfusion catheter of the type described in U.S. Pat. No.4,581,017 (Sahota) to allow blood flow through the catheter to distallyperfuse the artery while the balloon is inflated. As described in thatpatent, the disclosure of which is hereby incorporated by reference inits entirety, an opening is provided in the catheter shaft wallproximally of the balloon to allow blood to perfuse through the catheterdistally of the balloon.

It sometimes may occur that the ionic charge of the molecule may changeduring the procedure, for example, if the pH of the fluid changes. SuchpH change may result from interaction of the liquid with the electrodeas may be a function of the duration of the procedure. In order to avoidadverse changes in pH, the liquid may be aspirated periodically from thecatheter and replaced with fresh liquid. This procedure may be used withthe two lumen configuration described above and illustrated in FIGS. 1and 2. Alternately with the three lumen embodiment, represented by FIG.2A, a continuous flow of liquid may be established through the balloon,flow of liquid being toward and into the balloon through the inflationlumen 22A and out of and away from the balloon through the return lumen40. The return leg 20 at the proximal end of the catheter 10 preferablyis provided with a variable flow resistor 46 by which the back pressureof the returning outflowing liquid may be controlled. By operating theinflation device and variable restrictor 46, the pressure developedwithin the balloon and rate of continuous flow through the system may becontrolled as desired.

Thus, I have described the invention by which medication may be appliedselectively to a targeted internal organ or body lumen, such as anartery. It should be understood, while the invention has been describedwith regard to treatment of tissue adjacent a body lumen, the inventionmay be practiced in any location where it is desired to apply medicationto a vessel or organ having a lumen accessible by a catheter. Forexample, the apparatus may be utilized to treat the heart or coronaryarteries. The catheter may be passed into a lumen in a particular organor may even be inserted into a lumen formed in an organ or tumor for theexpress purpose of receiving the catheter.

It should be understood that the foregoing description of the inventionis intended merely to be illustrative thereof and that otherembodiments, modifications and equivalents may be apparent to thoseskilled in the art without departing from its spirit.

Having thus described the invention, what I desire to claim in theletters patent is:
 1. A method for inducing the permeation of a fluidhaving charged molecules into a blood vessel comprising the stepsof:providing electrodes external of the patient's body; insertingpercutaneously into a blood vessel a balloon catheter having an elongateflexible shaft, with a porous balloon at the distal end of said shaft,an internal electrode positioned inside said balloon on said shaft, anda lumen extending through said shaft and terminating in an outletdistally beyond said balloon, said lumen being adapted to receive bloodproximally of said balloon and to enable blood to flow through saidcatheter and be emitted distally of said balloon to permit distalperfusion during inflation of said balloon; inflating said balloon withsaid liquid; and developing an electric field flowing from said internalelectrode to said external electrode so that said liquid flows radiallyoutward through said pores in said balloon to the blood vessel to betreated.
 2. A method as defined in claim 1 wherein said internalelectrode is inserted into an artery in the region of a stenosis andwhere the liquid includes a compound adapted to treat the region of thestenosis.
 3. A method as recited in claim 1 wherein the internalelectrode is inserted into an artery adjacent the site of a stenosistreated by angioplasty and said liquid contains medication adapted toretard restenosis.
 4. A method as recited in either of claims 2 or 3further comprising the step of pulsing the electric field in phase withthe patient's cardiac rhythm.
 5. A catheter for selectively inducing thepermeation of liquid to a targeted portion of a blood vessel in the bodyof a patient comprising:an elongate flexible shaft dimensioned forinsertion into the human vascular system, the shaft having proximal anddistal ends; a balloon for emitting the liquid from the catheter; afirst lumen extending along said shaft for delivering the liquid fromthe proximal end of the catheter to the distal region of the catheter; asecond lumen extending through said shaft and terminating in an outletdistally beyond said balloon, said second lumen being adapted to receiveblood proximally of said balloon and to enable blood to flow through thecatheter and be emitted distally of said balloon to permit distalperfusion during inflation of said balloon; an internal electrodecarried by the catheter at the distal end of the catheter; and aconductor extending through said shaft and being electrically connectedto said internal electrode, the proximal end of the conductor beingconnectible to a source of electrical energy.
 6. An apparatus forselectively inducing the permeation of liquid to a targeted portion of ablood vessel in the body of a patient comprising:at least one externalelectrode adapted to be positioned outside of the patient's body; acatheter having an elongate flexible shaft dimensioned for insertioninto the vascular system, the catheter having proximal and distal ends,a balloon for emitting said liquid from said catheter; a first lumenextending along said catheter shaft for delivering said liquid from theproximal to the distal region of the catheter, a second lumen extendingthrough said catheter shaft and terminating in an outlet distally beyondsaid balloon, said second lumen being adapted to receive bloodproximally of said balloon and to enable blood to flow through saidcatheter and be emitted distally of said balloon to permit distalperfusion of blood during inflation of said balloon; an internalelectrode carried by said catheter at the distal end of said catheter; aconductor extending through said catheter shaft and being electricallyconnected to said internal electrode, the proximal end of said conductorbeing connectible to a source of electrical energy and, an electricalenergy source for inducing an electric field between said internalelectrode and said external electrode so that fluid emitted from thedistal end of said catheter will flow in a direction extending from theinternally placed electrode outwardly toward the external electrode. 7.A method of delivering a drug to a treatment site in a vessel whichcontains a flowing first fluid, the method comprising the stepsof:providing at least one electrode external of the patient's body;inserting percutaneously into the vessel a catheter having an elongateflexible shaft, with an inflatable balloon at the distal end of saidshaft, an internal electrode positioned in the area of said balloon, anda lumen extending through said shaft and terminating in an outletdistally beyond said balloon; inflating said balloon at the treatmentsite; delivering a drug in the area of the balloon; perfusing the firstfluid through an opening near the proximal end of said balloon to anopening located distally of said balloon; and developing an electricfield flowing from said internal electrode so that said drug flowsradially outward to the vessel to be treated.